TUMOR SUPPRESSOR GENE AND CHEMICAL CARCINOGENESIS

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DESCRIPTION: WT1 (Wilms tumor 1), a zinc finger-containing tumor suppressor protein plays a crucial role in the developing urogenital system and behaves as a transcriptional repressor of genes involved in growth. While characterizing the rat model for Wilm s tumors- the nitrosomethylurea (NMU)-induced embryonal nephromas, we discovered that the rat WT1 transcript undergoes RNA editing. RNA editing is a novel form of RNA modification that occurs co- or post-transcriptionally. The WT1 genomic sequence contains CTC (LEU) at codon 280 while the cDNA displays both CTC (LEU) and CCC (PRO) at this codon. RNA editing at the same nucleotide (T to C) also occurs in human WT1. WT1 mRNA editing is predicted to have biological significance, unlike the WT1-LEU protein, edited WT1-PRO has a lower capacity to repress the transcription of genes linked to the growth-related gene promoters such as EGR-1, and IGF2. On the other hand, the edited WT1-PRO protein represses transcription of genes linked to the differentiation-specific MK (midkine) gene promoter much more efficiently than unedited WT1-LEU. We have observed that while embryonal and newborn rat kidney contain undetectable levels of edited WT1 mRNA, the majority of NMU-induced kidney tumors (13/18), as well as human Wilms tumors (7/15) contain edited WT1 mRNA. We postulate that dysregulation of RNA editing and untimely expression of edited protein result in continued expression of growth factors and a suppression of differentiation factors, both of which contribute to malignancy in this system. To test this concept, we will determine whether over expression of the edited form of WT1 in rodent and human cells in vitro results in cell cycle arrest and/or apoptosis. Finally, we would like to characterize the sequence context and enzymatic activity that mediates RNA editing in the WT1 mRNA, with a future goal of cloning the gene encoding this activity.